The rewarding properties of food and addictive drugs, such as heroin and cocaine, are affected by metabolic state. Food deprivation enhances feeding, drug self-administration, relapse to drug-taking and self-stimulation reward. Midbrain dopamine (DA) neurons are thought to mediate the incentive motivational properties of food, addictive drugs and self-stimulation. Leptin, a major metabolic hormone, is secreted from fat cells, circulates in the blood and acts primarily in the brain. Leptin secretion is strongly determined by metabolic state and is suppressed during food deprivation. Food deprivation-induced changes in thyroid, adrenal and reproductive function are reversed by leptin administration and leptin administration also reverses food deprivation-induced potentiation of food, drug and self-stimulation reward. Recently, leptin receptors have been shown to be expressed by midbrain DA neurons. The proposed R21 project will develop mouse models to test the hypothesis that leptin acts directly on midbrain DA neurons to affect gene expression using conditional spatial and temporal expression of Cre recombinase and the leptin receptor gene harboring IoxP recombination sites. The effects of food deprivation and leptin on gene expression of DA neurons of the substantia nigra and ventral tegmental area will be determined using laser capture microdissection and microarray analysis. Completion of the project will provide the necessary tools for a second phase project in which specific genes will be examined for their role in mediating the direct or indirect action of leptin on midbrain DA neurons.